Summary: When T cells are stimulated by persistent self-antigens, they rapidly turn themselves off, in order to avoid autoimmunity. The problem is that, often, when challenged with slowly growing tumors and chronic infections, T cells mistakenly adopt the same fate and stop responding. Learning the mechanisms by which T cells get turned off will therefore allow us to revive failing immune responses against such pathologies. The significance of this study is that we have identified a new pathway that mediates the silencing of T cells to chronic- stimulation. The newly identified pathway operates downstream of a cell surface receptor known as JEDI (or PEAR1), that is only expressed when T cells encounter continuous stimulation. The expression of this molecule impairs the ability of T cells to continue making cytokines such as IL2. We hypothesize that PEAR1 acts by inhibiting the intracellular cascade downstream of the T cell receptor (TCR) which normally allows a T cell to sense the presence of antigen. In this proposal we will evaluate this hypothesis in two steps. First, we will examine the biochemical changes that happen in the TCR-proximal signaling network when PEAR1 expression is reduced. Second, we will evaluate the putative ligands of PEAR1 for their ability to activate its inhibitory activity. We expect that validation of the molecular mechanisms by which this negative regulatory pathway operates in T cells will allow us to develop new approaches to improve T cell responses in the context of tumors and chronic infections. Alternately, enhancing the signaling pathways downstream of PEAR1 can help dampen autoimmunity and transplant rejection. Towards this end, we will also generate data on the role of PEAR1 and its ligands in mouse models of malignancy and a parasitic infection.